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Malamas MS, Millen J. Quinazolineacetic acids and related analogues as aldose reductase inhibitors. J Med Chem. 1991;34(4):1492-503doi: 10.1021/jm00108a038.
Malamas, M. S., & Millen, J. (1991). Quinazolineacetic acids and related analogues as aldose reductase inhibitors. Journal of medicinal chemistry, 34(4), 1492-503. https://doi.org/10.1021/jm00108a038
Malamas, M S, and Millen, J. "Quinazolineacetic acids and related analogues as aldose reductase inhibitors." Journal of medicinal chemistry vol. 34,4 (1991): 1492-503. doi: https://doi.org/10.1021/jm00108a038
Malamas MS, Millen J. Quinazolineacetic acids and related analogues as aldose reductase inhibitors. J Med Chem. 1991 Apr;34(4):1492-503. doi: 10.1021/jm00108a038. PMID: 1901912.
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J Med Chem. 1991 Apr;34(4):1492-503. doi: 10.1021/jm00108a038.

Quinazolineacetic acids and related analogues as aldose reductase inhibitors.

Journal of medicinal chemistry

M S Malamas, J Millen

Affiliations

  1. Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.

PMID: 1901912 DOI: 10.1021/jm00108a038

Abstract

A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14,15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.

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